Clinical Effectiveness of SARS-CoV-2 Vaccination in Renal Transplant Recipients. Antibody Levels Impact in Pneumonia and Death : Transplantation

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Original Clinical Science—General

Clinical Effectiveness of SARS-CoV-2 Vaccination in Renal Transplant Recipients. Antibody Levels Impact in Pneumonia and Death

Rodríguez-Cubillo, Beatriz PhD1; Moreno de la Higuera, M. Angeles PhD1; Pérez-Flores, Isabel PhD1; Calvo Romero, Natividad PhD1; Aiffil, Arianne Sofía MD1; Arribi Vilela, Ana PhD2; Peix, Belen MD1; Huertas, Sara MD1; Juez, Almudena MD1; Sanchez-Fructuoso, Ana I. PhD1,3

Author Information
doi: 10.1097/TP.0000000000004261

Abstract

Erratum

In the article “Clinical Effectiveness of SARS-CoV-2 Vaccination in Renal Transplant Recipients. Antibody Levels Impact in Pneumonia and Death” by Rodríguez-Cubillo et al, which published online ahead of print on July 21, 2022 in Transplantation, an error was discovered by the authors on page 1 in the abstract:

Of the vaccinated patients, 67.02% developed a high antibody titer (>100 AU/mL) but 14.89% achieved a low antibody titer and 18.08%.

The correct sentence should read:

Of the vaccinated patients, 67.02% developed a high antibody titer (>100 AU/mL) but 14.89% achieved a low antibody titer and 18.08% nonantibodies.

Transplantation. 106(12):e529, December 2022.

INTRODUCTION

The coronavirus disease 2019 (COVID-19) pandemic has disproportionately impacted immunosuppressed patients, including renal transplant recipients (RTRs). COVID-19–associated mortality among RTRs was estimated at 18.6% to 23%.1

Currently, a variety of therapeutic options are available for the management of COVID-19 in this population that include antiviral medications, anti-inflammatory drugs, monoclonal antibodies, and immunomodulators agents.2,3

However, the key to minimizing the morbidity and mortality of COVID-19 among RTRs is probably vaccination, as many studies have demonstrated in general population.4,5

Consequently, since 2021, following national and international recommendations, a SARS-CoV-2 vaccination program was proposed in Spain and in many other countries. In the RTR population, a scheme was proposed based firstly on 2 and later 3 doses of messenger ribonucleic acid (mRNA) vaccines.6 However, since the first publications that investigated the response to the vaccine in transplanted patients, it was already apparent that this population would show a lower efficacy than the general population.7

On the one hand, in vitro published studies demonstrated poor immunogenicity of mRNA SARS-CoV-2 vaccine among RTRs in terms of humoral8-10 and cellular11,12 response. Boyarsky et al8 states that almost 30% of vaccinated patients do not achieve neutralizing antibody titers (anti–spike SARS cov2 or spike anti receptor binding domain) in the theoretical range of protection, and Stumpf et al12 suggests that cellular immunity is also ineffective in the 20% of vaccinated RTRs.

On the other hand, clinical effectiveness has been shown with a reduced rate of symptomatic COVID-19 and an 80% reduction in mortality compared with unvaccinated solid organ transplant recipients (SOTRs).13-15 Despite clinical benefit, vaccinated SOTRs do have greater risk of breakthrough COVID-19 than the general population.16

Several studies have demonstrated that up to 20% of vaccinated renal transplant patients had an unfavorable evolution in terms of mortality or intensive care unit admissions, despite having received the complete vaccine regimen with 2 doses.17,18

One important study19 showed that the percentage of patients with effective immunization after vaccination increased with a third dose versus only 2 doses. However, 51% of the patients did not develop anti–SARS-CoV-2 antibodies even after the third dose.19

Antibody titer has been tried to relate to the prediction of outcomes related to SARS-CoV-2 in different populations.20-22 Apparently, lower antibody titers are associated with poorer results, but this question has not been specifically investigated in the RTR population. Published studies describe antibody levels between 18 and 100 arbitrary unit (AU)/mL for “responder” patients15,16 with better results after infection with SARS-CoV-2 in those with higher antibody levels.21,23-28

To date, there are several studies focused on the study of the humoral and cellular response of RTRs after the vaccine; however, there are few publications that analyze the clinical effect of these vaccines on RTRs suffering from SARS-CoV-2 infection. Moreover, it is unclear the titer cutoff points of antibodies that associate with effective protection in this patient population.

The primary aim of this study is to evaluate the clinical impact of the SARS-CoV-2 vaccine in a kidney transplant population. Our secondary objective is to assess the correlation between antibody titer after SARS-CoV-2 vaccine administration and the impact in terms of pneumonia and death in infected kidney transplant recipients.

MATERIALS AND METHODS

Study Population and Design

This retrospective observational study included all kidney transplant patients with polymerase chain reaction or antigen confirmed SARS-CoV-2 infection who were referred to our institution (a referral kidney transplantation center) between March 15, 2020, and March 15, 2022. Final follow-up date was April 15, 2022. Early diagnosis was considered for patients with a positive test within the first 5 d of symptoms.

In the period of our study, several variants of the SARS-CoV-2 virus were responsible for the infection of our patients. Based on the epidemiological situation in our region, the Wuhan, the Alpha (B.1.1.7), Delta (B.1.617.2) and Omicron (B.1.1.529) variants were considered the cause of the cases. During the last period, between November 2021 and March 2022, the dominant variant was Omicron. In our study, this latter variant was compared with the former.

Patients included in the study range from the onset of the COVID-19 pandemic to the present. To minimize biases associated with the level of knowledge about the disease, the available therapies, or the use of the vaccine, the population was stratified in 3 periods of interest. This stratification was made based on the epidemiological characteristics of the waves that happened in our region.29 The first period was from March 15, 2020, to April 31, 2020, and the second period was from August 1, 2020, to April 31, 2021. The last period covers from July 1, 2021, to March 15, 2022.

Clinical, laboratory, and radiologic data were collected. Patients were monitored on admission and during the active infectious process. SARS-CoV-2 serostatus was disponible in vaccinated patients. All laboratory and imaging tests were performed as part of standard of care.

Unfavorable outcome was defined by the presence of pneumonia, progressive respiratory failure resulting in need of high oxygen doses (reservoir, continuous positive airway pressure, noninvasive mechanic ventilation, invasive mechanic ventilation), or death.

This study was conducted following the World Medical Association Declaration of Helsinki, national and local laws, and good clinical practice standards.

Approval was granted by the Ethical Committee of Hospital Clínico San Carlos.

Vaccination Protocol Against SARS-CoV-2

Our vaccination protocol against SARS-CoV-2 based on the recommendations of the community of Madrid 6 consists of the administration of 2 or 3 doses of vaccine against SARS-CoV-2 (BNT162b2 [Pfizer-BioNTech], mRNA-1273 [Moderna], or ASTRAZENECA vaccine). Availability in our center was from April 2021. We considered patients as fully vaccinated only if infection occurred >14 d after second dose.

Additional vaccination shall be performed with mRNA vaccine at least 28 d after the second dose. In people who were vaccinated with ASTRAZENECA, the additional dose will be made with mRNA vaccine.

Anti-spike Antibody Titers

According to hospital protocols in patients with COVID-19, we used Alinity Anti–SARS-CoV-2 spike anti receptor binding domain (Abbott Diagnostics) as the luminiscent immunoassay for quantitative determination of antibodies against SARS-CoV-2 spike protein. A concentration of ≥50 AUs per milliliter was the cutoff of the technique. Concentrations >40 000 AU/mL were diluted to achieve the exact one.

To identify the impact of antibody titer on results after SARS-CoV-2 infection, based on results achieved in solid organ transplant and RTRs,5-15 we classified the patients based on different cutoff points into 3 cohorts: nonantibody (0–20 AU/mL), low titer (20–100 AU/mL), or high titer (>100 AU/mL).

Routine controls with anti–SRBD IgG antibodies were performed at our consultations to evaluate the humoral response to the vaccine after each dose was administered (15–21 d after the second and third doses). Additionally, quantitative antispike antibody titer assay was obtained on admission. For the analyses, the highest value was considered.

We excluded patients younger than 18 y old, those infected in the next 14 d after the second dose of vaccine, or those in which the antibody titer after the vaccine was not available.

Patient Management

The general medical management of patients with SARS-CoV-2 has been adjusted to the recommendations of the moment, from March 2020 to the present.25,29,30

In terms of immunosuppressive management, our local protocols include immunosuppressive adjustment at the time of diagnosis. Therefore, mycophenolate acid (MPA) and/or rapamycin were discontinued or reduced associated with the addition of low prednisone doses. The reduction or suspension of calcineurin inhibitor (CNI) was recommended in patients with presence of respiratory failure. However, the stage of infection in which the diagnosis was made, and therefore the adjustment of immunosuppression, may vary according to when the patient decides to contact our center.

Thus, based on the management of immunosuppressive treatment, patients were differentiated into 2 groups: (a) early MPA minimization, if MPA reduction could be performed when the patient was asymptomatic, or (b) late minimization, if MPA reduction was performed when the patient already had symptoms of respiratory failure.

It should be noted that since December 2021, there is availability in our center in Remdesivir and Sotrovimab, so it is used since then in patients with clinical indication.

The use of sotrovimab was restricted in those patients with no immune response to the vaccine (antibody titer <100 AU/mL) who were not candidates for remdesivir because of renal failure and who were in an early stage of the disease (<5 d) or showed criteria of severity.31 We began to use remdesivir from December 2022 in patients with preserved renal function (GRF >25 mL/min) whose disease phase was early (<5 d) or more advanced but with data of severity.32-34

Statistical Analysis

Categorical variables were expressed with absolute/relative frequency and quantitative with median and interquartile rank and were compared with nonparametric test according to their distribution. The Kaplan-Meier method with log-rank test was used for survival analysis. To evaluate the association between anti–SRBD IgG antibodies titer categories and pneumonia and mortality related to COVID-19, a logistic regression univariate analysis was performed. Furthermore, to adjust for potential confounding covariates, a multivariable logistic regression analysis was performed.

Statistical analysis was performed with SPSS (released 2017; IBM SPSS Statistics for Windows, Version 25.0, Armonk, NY, IBM Corp).

RESULTS

Figure 1 shows the flow chart of patients included in our study. A total of 186 patients were included. The median follow-up time was 99 d (interquartile range [IQR], 76–559 d).

F1
FIGURE 1.:
Flow chart of patient included in the study. RTRs, renal transplant recipients; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2.

Firstly, we stratified the patients based on the 3 periods previously described (Table 1). We evaluated the patients’ baseline characteristics, including those related to comorbidities, transplantation, and immunosuppression treatment, as well as immunologic markers related to immunosuppression status.

TABLE 1. - Baseline characteristics of patients, according with infection period
Baseline characteristics Infection period P
Period 1 Period 2 Period 3
March 2020 to April 2020, N = 37 (19.8%) August 2020 to April 2021, N = 53 (28.5%) July 2021 to March 2022, N = 96 (51.6%)
Vaccine 0 0 94 (97.9)
Vaccine type
 BNT162b2 0 0 23 (24.4)
 mRNA-1273 0 0 65 (69.14)
 ASTRAZENECA 0 0 3 (3.19)
Vaccine dose
 2 doses 0 0 16 (17.01)
 3 doses 0 0 78 (82.9)
Titer, median (IQR) 442 (36–5658)
Titer <20 AU/mL 18 (18.75)
Titer >100 AU/mL 63 (65.6)
Age, median (IQR) 65 (57–71) 57 (48.5–64.5) 58 (46–69) 0.044
Female sex, n (%) 15 (40.5) 19 (35.8) 37 (38.5) 0.901
Transplantation time, mo, median (IQR) 106 (36–162) 92.3 (49.6–177) 105.5 (55–168) 0.704
Induction thymoglobulin, n (%) 18 (51.4) 24 (60) 56 (58.3) 0.714
Thymoglobulin (mg/kg) 1 (0–3.3) 2.76 (0–4.3) 2.56 (0–4.2) 0.523
Diabetes, n (%) 15 (40.5) 16 (30.2) 36 (37.9) 0.536
Obesity, n (%) 15 (42.9) 14 (28.6) 35 (36.4) 0.390
High immunologic risk, n (%) 5 (13.5) 8 (13.5) 12 (12.5) 0.876
Non-Caucasian race, n (%) 11 (29.7) 16 (30.1) 27 (28.1) 0.187
Neoplasia, n (%) 7 (18.9) 6 (11.3) 18 (18.7) 0.484
Pulmonary pathology, n (%) 9 (24.3) 10 (18.9) 15 (15.6) 0.472
Baseline immunosuppression treatment
 FK + MPA 25 (67.5) 40 (75.4) 74 (77.1) 0.115
 mTOR-i 12 (33) 13 (24.5) 15 (16.7)
CKD-EPI, mL/min, median (IQR) 40 (30–60) 44 (31–60.7) 44 (34–68) 0.404
IgG, median (IQR) 1000 (648–1195) 962 (868–1200) 1005 (854–1290) <0.001
Baseline lymphocytes, median (IQR) 1100 (825–1770 1300 (1100–1600) 1360 (1100–1845) 0.249
Baseline CD4, median (IQR) 384 (3294–613) 416 (362–772) 493 (352–721) 0.419
Baseline CD8, median (IQR) 4384 (207–548) 416 (298–547) 479 (303–732) 0.155
–, no apply (n/a); AU, arbitrary unit; CKD-EPI, Chronic Kidney Disease Epidemiology Collaboration equation; FK, tacrolimus; IQR, interquartile range; MPA, mycophenolate acid; mRNA, messenger ribonucleic acid; mTOR, mammalian target of rapamycin; mTOR-i, mTOR via inhibitors.

Significantly, older patients were observed in the first period, 65 y (57–71 y) versus 57 (49–69). No other relevant differences were obtained between the 3 populations.

With respect to status vaccination, 92 patients (49.5%) were infected before they received the vaccine, and 94 (50.5%) did so despite having received the complete SARS-CoV-2 vaccine regimen (2 or 3 doses). Of the 94 patients vaccinated, 16 received 2 doses (17%), and 78 (82.9%) received 3 doses. Among the vaccinated patients, most of the patients were vaccinated with the mRNA-1273 vaccine (n = 65, 69.1%). The median antibody titer was 442 AU/mL.

The second table describes the characteristics associated with SARS-CoV-2 infection in the different study periods (Table 2). In the first period, the only variant was Wuhan; in the second period, 38 patients were infected by the Wuhan variant (71.7%) and 14 patients by the Alpha variant (26.4%). In the third period, which coincides with the start of the vaccine, the most frequent variant was Omicron in 85.3%, followed by the Delta variant in 14.5%.

TABLE 2. - Admission characteristics, treatments, and outcomes according with infection period
Differences between patients infected with SARS-CoV-2 (n = 186) Period 1 Period 2 Period 3 P
March 2020 to April 2020, N = 37 (19.8%) August 2020 to April 2021, N = 53 (28.4%) July 2021 to March 2022, N = 96 (51.6%)
Diagnosis characteristics
 SARS-CoV-2 Wuhan variant 37 (100) 38 (71.7) 0 <0.001
 SARS-CoV-2 Alfa variant 0 14 (26.4) 0 <0.001
 SARS-CoV-2 Delta variant 0 1 (1.9) 14 (14.5) <0.001
 SARS-CoV-2 Omicron variant 0 0 82 (85.3) <0.001
 Early diagnosis, n (%) 6 (16.2) 27 (50.9) 87 (90.5) <0.001
 Income needs, n (%) 33 (89.2) 32 (60.4) 23 (23.9) <0.001
 Dyspnea, n (%) 18 (48.6) 15 (28.3) 12 (12.6) <0.001
 Pneumonia, n (%) 29 (78) 27 (50.9) 15 (15.6) <0.001
 D-dimer (ng/mL), median (IQR) 1189 (717–2265) 668 (452–1251) 660 (360–1107) 0.003
 Ferritin (ng/mL), median (IQR) 647 (234–1679) 279 (122–778) 202 (70–472) <0.001
 LDH (IU/L), median (IQR) 478 (38–719) 492 (394–611) 407 (336–473) 0.002
 PCR (ng/mL), median (IQR) 3.01 (1.63–10.6) 3.11 (0.70–8.50) 0.85 (0.29–2.36) <0.001
 Lymphocytes, median (IQR) 600 (400–1125) 800 (600–1000) 730 (500–990) 0.553
 CKD-EPI (mL/min), median (IQR) 29.45 (17.5–47) 38.5 (25–53.6) 40 (27.7–69.25) 0.047
 AKI, n (%) 22 (61.1) 25 (47.2) 18 (18.75) <0.001
Treatments
 Early MPA minimization, n (%) 8 (21.6) 21 (39.6) 78 (81.1) <0.001
 Stop MPA, n (%) 31 (88.6) 43 (93.5) 48 (50.3) <0.001
 Stop CNI, n (%) 25 (67.6) 27 (51.4) 15 (15.6) <0.001
 FK levels, median (IQR) 7.5 (6–8.6) 6.6 (5.5–8) 7.5 (6–9) 0.271
 CSA levels, median (IQR) 50 (40–60) 50 (40–67) 0.295
 Steroids bolus, n (%) 21 (56.8) 24 (45.3) 16 (16.6) <0.001
 Cumulative steroids, mg, median (IQR) a 375 (106–973) 290 (126–406) 50 (0–115) <0.001
 Anticoagulation, n (%) 26 (70.3) 37 (69.8) 32 (33.3) <0.001
 Tocilizumab, n (%) 9 (24.3) 7 (13.2) 1 (1.04) <0.001
 Remdesivir, n (%) 0 0 9 (9.3) <0.001
 Sotrovimab, n (%) 0 0 9 (9.3) 0.011
Results
 Radiological worsening, n (%) 19 (54.3) 20 (39.2) 8 (8.4) <0.001
 Maximum oxygen requirement
  Basal or NG, n (%) 26 (70.2) 43 (81.2) 88 (91.6) <0.001
  NIMV/R/CPAP, n (%) 6 (16.2) 6 (11.3) 5 (5.2)
  IMV, n (%) 5 (13.5) 4 (7.5) 3 (3.2)
 Over infection, n (%) 12 (33.3) 13 (24.5) 10 (10.5) <0.001
 Death, n (%) 8 (21.6) 8 (15.1) 5 (5.2) 0.017
 Discharge, n (%) 29 (78.4) 45 (84.9) 91 (94.7)
Units: D-dimer (ng/mL): normal range <500 ng/mL, ferritin (ng/mL): normal range 30–350 ng/mL, and LDH (UL/L): normal range 240–480 U/I.
aPrednisone units.
–, no apply (n/a); AKI, acute kidney injury; CKD-EPI, Chronic Kidney Disease Epidemiology Collaboration equation; CNI, calcineurin inhibitor; CPAP, continuous positive airway pressure; CSA, cyclosporine; FK, tacrolimus; IMV, invasive mechanic ventilation; IQR, interquartile range; LDH, lactate dehydrogenase; MPA, mycophenolate acid; NIMV, non invasive ventilation; NS, nasal glasses; PCR, polymerase chain reaction; R, reservoir; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2.

At the time of diagnosis, dyspnea and pneumonia were more common in infected patients in the first and second periods than in the third period (48.6%, 28.3% versus 12.6% and 78.0%, 50.9% versus 15.8%, respectively). Inflammation parameters were also lower in this group (Table 2). In fact, need to be admitted gradually decreased in the second and third periods (P1 = 89.2%, P2 = 60.4%, P3 = 23.9%; P 0.005).

In the first period, 61.1% of patients (n = 22) presented with acute renal injury (AKI) at admission, of which 22.2% (n = 8) did not recover their renal function. However, in the group of third period, only 18.7% (n = 18) suffered AKI during the infectious process, and only 4 (4.2%) of them did not recover their basal renal function (P = 0.001).

Table 2 provides a summary of pharmacological management for different groups.

Early minimization of MPA was performed in the 21.6% of patients infected in the first period, but this practice was more frequent in the second and third period (39.6% and 81.1%; P < 0.001).

Nevertheless, in the first and second periods, suspension of MPA and CNI was required more frequently than in the third period (88.6%, 93.5% versus 50.3% and 67.6%, 51.4% versus 15.6%, respectively; P = 0.001).

Notably, doses of steroids were gradually lower in the first, second, and third period, respectively (prednisone equivalent doses: P1 = 375 mg [IQR, 106–973 mg] versus P2 = 290 mg [IQR, 126–406 mg] versus P3 = 50 [0–115 mg]; P 0.001). Similarly, rescue treatments such as tocilizumab or intravenous steroids at high dose were used exceptionally in the third period compared with the first and second periods (P1 = 24.3% and 56.8%, P2 = 13.2% and 45.3%, and P3 = 1.04% and 16.6%, respectively; P 0.005).

Moreover, indications for prophylactic or therapeutic anticoagulation were lower among patients infected in the third period (P1 = 70.3%, P2 = 69.8%, P3 = 33.3%; p 0.001).

Importantly, patients included in the third period received additional treatment with sotrovimab (9.3%) or remdesivir (9.3%). No patients included in period 1 or 2 received this type of therapy.

Finally, the clinical evolution was more favorable gradually over time, being better in the third period than in the first and second period. Table 2 shows the clinical results in terms of pneumonia, radiological progression, need for IMV or high oxygen, over infection, and death in patients infected in the first, second, and third periods.

The incidence of death was 21.6% in period 1 versus 15.1% in period 2 and 5.2% in the last period (P = 0.017).

Based on these results so improved in the third period, we consider that the effect of the vaccine and the subsequent adequate immunization would have a great influence on the clinical evolution of the infected RTRs.

Therefore, we wanted to investigate the impact of antibody titers on this patient population. Therefore, based on the findings of earlier studies, antibody titers were stratified into 3 categories: (a) high titer: >100 AU/mL, (b) low titer: 100–20 AU/mL, and (c) nonantibodies: <20 AU/mL.

We observed that the 67.02% (n = 63) of vaccinated patients infected with SARS-CoV-2 had developed antibodies a high titer (>100 AU/mL). Of patients with a lower humoral response, 14.89% (n = 14) were included in the group of 20 to 100 and 18.08% (n = 17) in the group of 0 to 20 AU/mL.

Table 3 shows baseline characteristics of patients on base of the 3 categories. No differences were observed between the 3 categories except in terms of renal function and age. In the group of patients with antibodies >100 AU/mL, they were younger (55 versus 63.5 versus 69 y; P = 0.009) and had better renal function (Chronic Kidney Disease Epidemiology Collaboration equation 51 versus 40 versus 39 mL/min; P = 0.016). With respect to the immunosuppressive regime at the time of diagnosis, most patients were previously treated with sodium MPA and tacrolimus in both groups (no vaccine: n = 65, 71.4% and vaccine: n = 74, 84.2%). No significant differences were founded in mammalian target of rapamycin inhibitors treatment between groups (Table 3).

TABLE 3. - Baseline characteristics of patients based on vaccine and serological status
Baseline characteristics (n = 186) No vaccine, N = 92 (49.5%) Vaccine, N = 94 (50.5%) P
No vaccinated, N = 92 (49.5%) Titer 0–20 AU/mL, N = 17 (18.08%) Titer 21–100 AU/mL, N = 14 (14.89%) Titer >100 AU/mL, N = 63 (67.1%)
Vaccine type
 BNT162b2 5 (29.4) 5 (35.7) 12 (19.04) 0.465
 mRNA-1273 10 (58.8) 8 (57.1) 47 (74.6)
 ASTRAZENECA 0 (0) 1 (7.1) 2 (3.2)
Vaccine dose
 2 doses 5 (29.4) 4 (28.5) 7 (11.1) 0.094
 3 doses 12 (12.7) 10 (10.6) 57 (60)
Titer median, IQR 1.6 53.05 2605 (442–10 328) 0.022
Age, median (IQR) 60 (51–67) 69 (60–75) 63.5 (48–74) 55 (45–65) 0.009
Female sex, n (%) 36 (39.1) 6 (17.1) 4 (11.4) 25 (71.4) 0.698
Transplantation time, mo, median (IQR) 101.7 (49.8–169.2) 122 (34–184) 152.3 (81.5–246.9) 81.9 (48.7–157.7) 0.164
Thymoglobulin (mg/kg) 1.40 (0.5–4) 2.7 (0–4.6) 3 (0–4.2) 1 (0–4) 0.789
Diabetes, n (%) 32 (34.8) 8 (22.9) 6 (17.1) 21 (60) 0.427
High immunologic risk, n (%) 14 (15.2) 2 (20) 2 (20) 6 (60) 0.894
Non-Caucasian race, n (%) 28 (30.43) 3 (29) 1 (6.7) 11 (73) 0.535
Neoplasia, n (%) 14 (15.2) 2 (12.5) 4 (25) 10 (62.5) 0.479
Baseline immunosuppression treatment
 FK + MPA 65 (71.4) 16 (100) 12 (85.7) 46 (79.3) 0.064
 mTOR-i 26 (28.3) 0 (0) 2 (14.3) 12 (85.7)
CKD-EPI (mL/min), median (IQR) 41.20 (30–60) 39 (30–44) 40 (27–67) 51 (40–83) 0.016
IgG, median (IQR) 767 (593–1008) 1000 (648–1195) 962 (868–1200) 1005 (854–1290) 0.003
Baseline lymphocytes, median (IQR) 1300 (1000–1900) 1265 (810–1570) 1500 (1320–2180) 1333 (1092–1845) 0.493
Baseline CD4, median (IQR) 443 (334–722) 534 (318–602) 436 (315–603) 522 (378–814) 0.290
Baseline CD8, median (IQR) 405 (207–680) 450 (270–708) 756 (392–794) 497 (352–675) 0.373
CD4/CD8, median (IQR) 0.99 (0.60–1.78) 1.10 (0.73–1.9) 0.74 (0.47–1.32) 1.16 (0.75–1.62) 0.928
AU, arbitrary unit; CKD-EPI, Chronic Kidney Disease Epidemiology Collaboration equation; FK, tacrolimus; IQR, interquartile range; MPA, mycophenolate acid; mRNA, messenger ribonucleic acid; mTOR, mammalian target of rapamycin; mTOR-i, mTOR via inhibitors.

In relation to epidemiological factors, we were able to find general differences between vaccinated and unvaccinated patients. The Omicron variant was the most predominant in the group of vaccinated patients (81.3%), whereas in unvaccinated patients, only 2.2% were affected by this variant. Early diagnosis was more frequent among vaccinated patients (92.3% versus 35.9%).

Table 4 shows the differences that we observed between categories in the presentation of the disease.

TABLE 4. - Admission characteristics, treatments, and outcomes according with vaccine status
Differences between patients infected with SARS-CoV-2 (n = 186) No vaccine, N = 92 (49.5%) Vaccine, N = 94 (50.5%) P
Titer 0–20 AU/mL, N = 17 (18.08%) Titer 21–100 AU/mL, N = 14 (14.89%) Titer >100 AU/mL, N = 63 (67.02%) No vaccine vs vaccine/between Ab categories
Admission characteristics
 SARS-CoV-2 Omicron variant 2 (2.2) 13 (76.5) 10 (71.4) 57 (90.5) <0.001/0.154)
 Early diagnosis, n (%) 33 (35.9) 15 (88.2) 12 (85.7) 60 (95.2) <0.001
 Income needs, n (%) 67 (72.8) 8 (47) 5 (35) 8 (12) 0.005
 Dyspnea, n (%) 33 (35.9) 5 (31.3) 5 (35.7) 2 (3.3) <0.001
 Pneumonia, n (%) 57 (62.0) 6 (35.3) 5 (35.7) 3 (4.8) <0.001
 D-dimer (ng/mL), median (IQR) 867 (510–1610) 1495 (949–4840) 518 (332–699) 506 (340–760) 0.014/0.078
 Ferritin (ng/mL), median (IQR) 364 (154–899) 434 (215–726) 223 (115–338) 114 (57–348) 0.032
 LDH (IU/L), median (IQR) 495 (397–670) 432 (389–550) 306 (270–425) 397 (359–426) <0.001/0.513
 RCP (ng/mL), median (IQR) 3.1 (0.9–8.5) 1.8 (0.29–2.19) 0.29 (0.29–0.89) 0.82 (0.29–0.99) <0.001/0.105
 Lymphocytes, median (IQR) 700 (500–1000) 680 (412–1265) 620 (290–720) 910 (515–1245) 0.604
 CKD-EPI (mL/min), median (IQR) 34.45 (20.5–50) 32 (22–40) 34 (24–54) 53 (35–85) 0.002
 AKI, n (%) 48 (52.2) 5 (29.4) 4 (28.6) 8 (12.7) <0.001
Treatments
 Early MPA minimization 29 (33.7) 63% 84% <0.001/0.230
 Stop MPA, n (%) 83 (90.2) 11 (64.7) 9 (69.2) 26 (41.9) 0.009/0.082
 Stop CNI, n (%) 53 (57.06) 7 (41.2) 4 (30.8) 3 (4.8) 0.034/<0.001
 FK levels, median (IQR) 6.9 (5.6–8.1) 7.5 (5–8.6) 6.3 (4.1–9.4) 7.5 (6.5–9) 0.234/0.322
 CSA levels, median (IQR) 50 (40–70) 113 (60–130) 0.043
 Steroids bolus, n (%) 47 (51.1) 6 (35.3) 5 (35.7) 3 (4.8) <0.001
 Cumulative steroids, mg, median (IQR) a 300 (125–625) 281 (22–656) 181 (70–400) 70 (35–130) <0.001
 Anticoagulation, n (%) 65 (70.7) 8 (47.1) 7 (50) 15 (23.8) <0.001/0.055
 Tocilizumab, n (%) 16 (17.4) 1 (5.9) 0 0 <0.001
 Remdesivir, n (%) 1 (1.1) 2 (11.8) 2 (14.3) 4 (6.3) <0.001/0.546
 Sotrovimab, n (%) 0 4 (23.5) 3 (21.4) 2 (3.2) <0.001/0.011
Results
 Radiological worsening, n (%) 40 (43.5) 4 (23.5) 3 (21.4) 0 <0.001
 Maximum oxygen requirement
  Basal or NG, n (%) 70 (76.1) 13 (76.5) 11 (78.6) 63 (100) 0.004
  NIMV/R/CPAP, n (%) 12 (13.0) 3 (17.6) 2 (14.3) 0
  IMV, n (%) 10 (10.9) 1 (5.9) 1 (7.1) 0
 Over infection, n (%) 26 (28.3) 6 (35.4) 2 (14.3) 1 (1.6) <0.001
 Death, n (%) 17 (18.5) 3 (17.6) 1 (7.1) 0 0.005
 Discharge, n (%) 75 (81.5) 14 (82.4) 13 (92.9) 63 (100)
Units: D-dimer (ng/mL): normal range <500 ng/mL, ferritin (ng/mL): normal range 30–350 ng/mL, and LDH (UL/L): normal range 240–480 U/I.
aPrednisone units.
–, no apply (n/a); Ab, antibody; AU, arbitrary unit; AKI, acute kidney injury; CKD-EPI, Chronic Kidney Disease Epidemiology Collaboration equation; CNI, calcineurin inhibitor; CSA, cyclosporine; CPAP, continuous positive airway pressure; FK, tacrolimus; IMV, invasive mechanic ventilation; IQR, interquartile range; LDH, lactate dehydrogenase; MPA, mycophenolate acid; NIMV, non invasive ventilation; NS, nasal glasses; PCR, polymerase chain reaction; R, reservoir; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2.

At the time of diagnosis, dyspnea and pneumonia were more common in nonvaccinated patients than in the group of vaccinated patients, especially in the group of patients with high antibody titers (35.9% versus 3.3% and 62.0% versus 4.8%, respectively). Inflammation parameters were also lower in this group (Table 2). Kidney function was also less affected in vaccinated patients with high levels of antibodies. In fact, need to be admitted gradually decreased in the highest antibody titer groups (no vaccine: 72%, no antibody: 47%, low antibody: 35%, high antibody: 12%; P = 0.005).

Table 4 provides a summary of pharmacological management for different groups.

Early minimization of MPA was performed in the 33.7% of unvaccinated patients, but this practice was more frequent in vaccinated patients (64.3%, 84.1%; P < 0.001). There were no statistically significant differences between categories of vaccinated patients (P = 0.230).

Nevertheless, in nonvaccinated patients, suspension of MPA and CNI was required more frequently than in vaccinated patients, especially in the high-antibody group (90.2% versus 41.9% and 57.6% versus 4.8%, respectively).

Notably, in the group of vaccinated patients, doses of steroids were gradually lower between antibody categories than in unvaccinated patients (prednisone equivalent doses: 70 mg [IQR, 35–130 mg] versus 300 mg [IQR, 125–625 mg]). Similarly, rescue treatments (tocilizumab or intravenous steroids at high dose) were used exceptionally in the vaccine groups compared with the no vaccine group (no vaccine: 17.4% and 51.1%, no antibody: 5.9% and 35.3%, low antibody: 0% and 35.7%, high antibody: 0% and 4.8%, respectively; P = 0.005).

Moreover, indications for prophylactic or therapeutic anticoagulation were lower among vaccinated patients (no vaccine: 70.7%, no antibody: 47.1%, low antibody: 50%, high antibody: 23.8%; P < 0.001).

Importantly, patients with lower antibody titers received additional treatment with sotrovimab (44.4% versus 33% versus 22%; P = 0.011) or remdesivir (11.8% versus 14.3% versus 6.3%; P = 0.053) more frequently than patients with antibody titers >100 AU/mL. We also used remdesivir on a patient who had not been vaccinated (1.1%).

Finally, a significantly better evolution was observed in the vaccinated patients, especially in those patients with a higher antibody titer. Table 4 shows that poorer clinical results were observed in terms of pneumonia, radiological progression, need for IMV or high oxygen doses, over infection, and death in patients who were unable to develop a high antibody titer (>100 AU/mL). Indeed, we could observe that these results were gradual based on the categories proposed according to the title of antibodies (Table 4).

Survival curves were performed for the study of pneumonia and death based on these categories. Pneumonia-free survival at day 20 was 95% in the group of RTRs with >100 AU/mL antibodies, but unvaccinated patients were the group with the lowest pneumonia-free survival (40%; P < 0.001). Pneumonia-free survival at day 20 was similar in the low or nonantibodies groups (64% and 66%, respectively) (Figure 2).

F2
FIGURE 2.:
Pneumonia survival free according to antibodies SARS-CoV-2 titers after vaccine. AU, arbitrary unit; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2.

In terms of death, 4.2% (n = 4) patients died in the group of vaccinated against 18.5% (n = 17) in the group of unvaccinated patients. Figure 3 shows the gradual effect of antibody titers on mortality of RTRs. Only patients in the group with antibody titers >100 showed a 100% survival on day 60 postinfection. Patient survival at 60 d was 92% in patients with antibody level between 100 and 20 AU/mL. Interestingly, survival at day 60 was similar in RTRs with levels <20 AU/mL to that in those nonvaccinated RTRs (82%).

F3
FIGURE 3.:
Patient survival according to antibodies SARS-CoV-2 titers after vaccine. AU, arbitrary unit; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2.

Factors Associated With Risk of Mortality

We evaluated the protective role of the vaccine against SARS-CoV-2 infection in RTRs performing a multivariate analysis that included other risk factors for death previously cited in the literature. The period of infection, the comorbidities of the patients, the type of immunosuppressive treatment before infection, the causative variant, the management of immunosuppression during infection, and other therapies used were taken into account. We also considered the use of previous thymoglobulin or the time of transplantation until infection. Additionally, the impact of the antibody titer developed after the vaccine on mortality of the RTRs included was also evaluated. Inflammation parameters and AKI were not included in the multivariate analysis because of a high degree of collinearity (Table 5).

TABLE 5. - Multivariate regression logistic analysis
Risk factors for death RR (CI 95%) P RR (IC 95%) P
Period
 March 2020 to April 2020 Reference Reference
 August 2020 to April 2021 0.060 (0.005-0.697) 0.025
 July 21 to March 2022 0.051 (0.004-0.594) 0.018
Vaccine + >20 AU/mL 0.061 (0.008-0.466) 0.007 0.036 (0.006-0.507) 0.014
Type of vaccine (mRNA-1273) 0.156 (0.013-1.815) 0.138
SARS-CoV-2 Omicron variant 0.124 (0.028-0.548) 0.006 0.101 (0.008-1.283) 0.077
Age >75 y old 2.21 (0.61-6.60) 0.225
Age <50 y old 0.11 (0.01-0.88) 0.038
Female sex 1.09 (0.40-2.62) 0.952
Thymo induction 0.71 (0.268-1.906) 0.502
Transplant time <12 mo 6.50 1.34-31.38) 0.020 1.765 (0.330-9.424) 0.506
CKD-EPI <15 mL/min 5.51 (0.86-33.08) 0.077
Diabetes 3.28 (1.28-8.39) 0.013 3.347 (1.093-10.25) 0.035
Obesity 1.24 (0.479-3.235) 0.652
High immune risk 1.68 (0.51-5.50) 0.390
Non-Caucasian race 2.20 (0.837-5.83) 0.110
Pulmonary pathology 2.63 (0.97-7.16) 0.057
Neoplasia 2.32 (0.82-6.52) 0.114
Basal lymphocytes <800 u 2.83 (0.916-8.76) 0.071
IgG <600 3.81 (1.14-12.69) 0.029
CD4 <200 1.35 (0.15-11.95) 0.758
CD8 >500 1.24 (0.34-4.53) 0.732
Early diagnosis 0.14 (0.48-0.39) <0.001
Dyspnea, n (%) 6.42 (2.45-16.72) <0.001
D-dimer >800 ng/mL 5.58 (1.71-17.87) 0.004
Ferritin >700 (ng/mL) 3.83 (1.19-12.3) 0.023
LDH >500 IU/L 7.42 (2.48-22.15) 0.001
PCR >2 ng/mL 5.40 (1.77-17.10) 0.004
Lymphocytes <400 1.89 (0.63-5.84) 0.264
AKI 8.44 (1.79-39.7) 0.007
Early MPA minimization 0.10 (0.03-0.35) <0.001 0.129 (0.023-0.715) 0.019
Units: D-dimer (ng/mL): normal range <500 ng/mL, ferritin (ng/mL): normal range 30–350 ng/mL, and LDH (UL/L): normal range 240–480 U/I.
Ab, antibody; AU, arbitrary unit; AKI, acute kidney injury; CKD-EPI, Chronic Kidney Disease Epidemiology Collaboration equation; LDH, lactate dehydrogenase; MPA, mycophenolate acid; mRNA, messenger ribonucleic acid; RR, relative risk; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2.

Taking the first period as a reference, the second and third periods were shown as protective factors of mortality (P2: relative risk [RR], 0.053; 95% confidence interval [CI], 0.004-0.800; P = 0.034 and P3: RR, 0.040; 95% CI, 0.003-0.613; P = 0.021). A significant decrease in mortality risk was observed in the multivariable model for patients vaccinated against SARS-CoV-2 who were able to develop antibodies (even at a low rate of 20 AU/mL) in comparison to nonvaccinated patients or those with <20 AU/mL (RR, 0.036; 95% CI, 0.003-0.507; P = 0.014). We observed a protective effect of death associated with the Omicron variant compared with the other variants, but this association was not statistically significant (P = 0.077).

History of diabetes could negatively influence the evolution of affected patients (RR, 3.347; 95% CI, 1.095-10.26; P = 0.035); however, early minimization of MPA could reduce the risk of death in this patient population (RR, 0.129; 95% CI, 0.023-0.715; P = 0.019) (Table 5).

DISCUSSION

Based on our results, during the Omicron variant surge, COVID-19 breakthrough infections among RTRs had favorable outcomes compared with the same unvaccinated population in previous COVID-19 waves. In the low-antispike antibody titer groups, a higher pneumonia and mortality rate were identified.

Our results are in accordance with studies that show a clinical benefit of vaccine in SOTRs.13-15 Ravanan et al13 revealed a reduction of 80% in risk of symptomatic COVID-19 compared with unvaccinated SOTR.

However, it has been shown that, in renal transplant patients, the development of humoral and cellular immunization after anti–SARS-CoV-2 vaccine is lower than in the general population, which can imply a lesser protection against the virus.7

On the one hand, several studies show poor immunization up to 20% to 40% in RTRs in terms of cellular immunity11,12 and 20% to 30% in terms of humoral immunity.8-10

On the other hand, studies conducted on SOTRs and RTRs have shown that, despite having received a complete vaccine regimen, the results in infected patients remain poor.

In a large multicenter study of 18 215 fully vaccinated SOTRs at 17 transplant centers, breakthrough infections occurred in 0.23% to 2.52%, compared with 0.01% in immunocompetent vaccinated hosts.16 Mortality among breakthrough cases was 9.3%.

Rodríguez-Espinosa et al23 showed the results of a cohort of RTRs who became infected despite receiving 2 doses of vaccine when Delta variant was dominant. In this study, RTRs continued to have a similarly high number of hospital admissions (59.1%) and mortality (9.1%) in comparison with a similar population in 2020. The more favorable results shown in our study may be associated with the fact that most of our patients had already received the third dose, confirming the benefit of this additional dose among other factors.19

Despite the benefits of the vaccine, even of a third dose, up to 30% of our patients remain with a low titer of antibodies, which could be associated a worse clinical outcome.19

Diverse studies have demonstrated the efficacy of the mRNA vaccines in terms of antibody development against SARS-CoV-2,20-22,35 but to date, there is controversial the value of antibody titers to consider that a patient is actually protected from symptomatic or severe SARS-CoV-2 infection.

The study by Feng et al20 carried out in the general population observed that titers >260 AU/mL provide protection against disease (symptomatic and asymptomatic) by SARS-CoV-2. However, in this study, neither RTRs nor severely ill patients were included. As far as the titer of antibodies predicting protection against COVID-19 in RTRs is concerned, little information exists to date. Sanghavi et al21 described in a study that included SOTRs, that patients with low-titer patient had higher need for intensive care unit care (51.1 versus 11%) and higher mortality (21.3% versus 6.8%) than high-titer patients. The cutoff point of the antibody titers proposed in these studies is 132 AU/mL.21

Our results also described that patient who did not develop a broad humoral immunity after vaccination (<100 AU/mL) also showed an unfavorable evolution, in terms of the development of death and pneumonia, compared with those who did have a greater response. In fact, patients who do not develop antibodies postvaccine (0–20 AU/mL) had similar mortality rate to those who did not receive the vaccine in earlier COVID-19 waves (18%) (Figure 3). These results are reinforced in the multivariate analysis because a vaccination against SARS-CoV-2 that achieves the development of antibodies (>20 AU/mL) is considered a factor of death protection in RTRs infected by SARS-CoV-2 (RR, 0.067; 95% CI, 0.006-0.761; P = 0.029). These results are maintained after adjusting for periods of infection, whose impact is also evident, being protective the infection in the second and third periods versus the first period.

These results could reflect that the status of immunosuppression in these patients is so marked that their immune system is not able to develop antibodies against the vaccine or overcome the infection.7,16 Benotmane et al19 consider in a study that protection against symptomatic COVID-19 is not absolute with any vaccine, and probably, there is probably no single antibody threshold value to ensure a favorable outcome. Instead, the probability of infection decreases on average with higher immune responses, but substantial variation exists between individuals. Our results support the idea that it might be more appropriate to consider broader antibody ranges than to establish a single cutoff point. Indeed, according with other publications,3,23,24 our results support that other factors such as a history of diabetes were associated with an increased risk of death, but early minimization of MPA was associated with a lower risk of mortality.

Our study focuses on an RTR population and highlights that knowing the titer of antibodies in these patients may be helpful in making decisions, as lower antispike antibodies in this population correlate with worse outcomes.

Probably, the identification of these patients unable to develop antibodies may be necessary to better adapt their management.26 On the one hand, the administration of another additional vaccine dose27,28 could be to improve the humoral immunization rate in these selected patients. On the other hand, the management of immunosuppressants may be more individualized. To date, it is not clear what the exact management of immunosuppression is in the RTRs infected by SARS-CoV-2, although the minimization of MPA has been fairly accepted.25 Our study shows that early minimization of MPA can even reduce the risk of death in these patients.

However, early minimization of CNI may also be necessary in high-risk patients (ie, low or no antibodies titers), but a marked reduction of immunosuppressants may not be necessary in patients with an adequate immunization.

Finally, the administration of targeted therapies such as antivirals29,30 monoclonal antibodies,31 a fourth booster vaccine dose, or passive immunization by administering drugs such as casirivimab/imdevimab36 or cilgavimab/tixagevimab37 could be a very useful tool in high-risk RTRs. An effective selection of RTRs who may be benefited would be necessary to make the use of these drugs more useful and cost effective.

Our study has some limitations. Firstly, it is a retrospective study, with a small sample, which could associate biases related to studio design. Besides, the use of new drugs more targeted against infection has also been able to influence the most favorable evolution of infection in this latest wave of COVID-19.

However, vaccine clinical efficacy data have not yet been published after receiving 3 doses of vaccine in the context of the Omicron variant in an RTR population. Our results would be the first publication to collect this data. Additionally, it is the first publication that analyzes the impact of antibody titers on the clinical evolution of RTRs with SARS-CoV-2 infection. Moreover, these results are maintained after adjusting for SARS-CoV-2 variants and main key periods of the pandemic.

Nevertheless, more studies are needed to be able to propose more specific recommendations about claims for booster vaccine doses, immunosuppression management, and use of new targeted therapies in the RTR population.

CONCLUSIONS

  1. The vaccine against SARS-CoV-2 in the population of RTRs who were able to develop a minimum levels of antibodies is beneficial, as it decreases the risk of pneumonia and death.
  2. There is a percentage of patients who do not develop effective immunization, which poses a greater risk of pneumonia and death.
  3. It is important to identify patients with low vaccine response to propose an additional vaccine dose, passive immunization, and/or the administration of targeted therapies (antivirals, monoclonal antibodies) in case of infection to improve their outcomes.
  4. To ensure a favorable evolution of SARS-CoV-2 infection in the RTRs, the immunosuppression adjustment must be early, according to the baseline characteristics of the patient and the immunization status against SARS-CoV-2. Therefore, an early diagnosis of the infection is necessary, allowing decisions adapted to each patient.

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